Cell migration in tumors
Hideki Yamaguchi1, Jeffrey Wyckoff1,2 and John Condeelis1,2
Invasion of cancer cells into surrounding tissue and the
vasculature is an initial step in tumor metastasis. This requires
chemotactic migration of cancer cells, steered by protrusive
activity of the cell membrane and its attachment to the
extracellular matrix. Recent advances in intravital imaging and
the development of an in vivo invasion assay have provided
new insights into how cancer cell migration is regulated by
elements of the local microenvironment, including the
extracellular matrix architecture and other cell types found in
primary tumors. These results, combined with new findings
from in vitro studies, have led to new insights into the molecular
mechanisms of cell protrusive activity and chemotactic
migration during invasion and metastasis.
Addresses
1
Department of Anatomy and Structural Biology
2
Analytical Imaging Facility, Albert Einstein College of Medicine,
1300 Morris Park Avenue, Bronx, New York 10461, USA
Corresponding author: Condeelis, John (condeeli@aecom.yu.edu)
Current Opinion in Cell Biology 2005, 17:559–564
This review comes from a themed issue on
Cell-to-cell contact and extracellular matrix
Edited by Inke Näthke and W James Nelson
Available online 10th August 2005
0955-0674/$ – see front matter
# 2005 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.ceb.2005.08.002
Introduction
Metastasis — the dissemination of cancer cells from the
primary tumor to a distant organ — is the most frequent
cause of death for patients with cancer. However, the
molecular mechanisms of metastasis are poorly under-
stood as a result of their apparent complexity. Cancer cell
migration and invasion into adjacent tissues and intrava-
sation into blood/lymphatic vessels are required for
metastasis of adenocarcinomas, the most common human
cancers [1,2]. Invasive carcinoma cells acquire a migratory
phenotype associated with increased expression of sev-
eral genes involved in cell motility [3,4]. This allows
carcinoma cells to respond to cues from the microenvir-
onment that trigger tumor invasion. Therefore, molecules
involved in cancer cell migration could be potential
targets for anti-metastasis therapy. However, most studies
on cell motility have been performed in two-dimensional
(2D) culture systems, which limits our understanding of
mechanisms of cell migration, as cells use different cell
migration strategies in physiological three-dimensional
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(3D) culture systems [5,6]. Moreover, recent advances
in in vivo imaging have yielded new insights into the
migration of carcinoma and host cells in tumors and
demonstrate that the regulation of cancer cell migration
in vivo is more complicated than had been supposed,
involving chemoattractants, the extracellular matrix, and
signaling interactions with stromal cells [2,7,8].
In this review, we summarize recent progress uncovering
how mammary carcinoma cells migrate in primary tumors
and how the migration is regulated by macrophages. We
also integrate recent findings on molecular mechanisms of
carcinoma cell and macrophage migration, with emphasis
on the protrusive structures formed by these cell types
that steer the cells toward blood vessels and that facilitate
invasion and intravasation.
Cancer cell migration on and through the
extracellular matrix in tumors in vivo
Cancer cell migration in primary tumors can be directly
observed by multiphoton microscopy with animals carry-
ing green fluorescent protein (GFP)-labeled tumors [7].
In the case of breast tumors, most of the migrating cells are
solitary with an amoeboid morphology [9]. These cells are
often observed moving linearly in association with the
extracellular matrix (ECM) fibers (Figure 1a). Given that
some of the ECM fibers converge onto blood vessels, these
fibers function as a path for carcinoma cells to migrate
toward blood vessels. Directed migration of cancer cells is
mediated by chemoattractants diffusing from blood ves-
sels and produced by other cell types. Epidermal growth
factor (EGF) receptor expression and chemotactic beha-
vior in vitro are well correlated with the ability of mammary
carcinoma cells to invade and metastasize [3,9]. There-
fore, EGF is thought to be a central chemoattractant for
breast cancer invasion. Once carcinoma cells reach blood
vessels by chemotactic migration, then they must enter the
blood space to travel to distant organs. This process, called
intravasation, requires carcinoma cells to penetrate the
dense basement membrane ECM surrounding blood ves-
sel walls and squeeze through the endothelial cell barrier.
Intravital imaging of carcinoma cells in the intravasation
process demonstrated that these cells extend invadopod-
like protrusions that penetrate the barriers of the blood
vessel wall within minutes [9] (Figure 1b). This observa-
tion indicates that cancer cells form specialized protrusive
structures with an ECM-remodeling activity in vivo.
A paracrine loop between cancer cells and
macrophages
Tumor progression and invasion are controlled by cross-
talk between cancer cells and other cell types within the
Current Opinion in Cell Biology 2005, 17:559–564
560 Cell–to–cell contact and ECM

Figure 1

Cell protrusions and the paracrine loop between carcinoma cells and macrophages in intravasation. (a) Model for intravasation of breast cancer
cells. Carcinoma cells, which acquire a migratory phenotype via changes in gene expression resulting from signals from the microenvironment,
degrade underlying basement membrane and detach from the primary tumor. These cells migrate on extracellular matrix (ECM) fibers toward
blood vessels in response to chemoattractants such as epidermal growth factor (EGF). Once cancer cells reach blood vessels they breach the
basement membrane surrounding blood vessel walls and endothelial cells to intravasate into the blood stream. Tumor-associated macrophages
promote carcinoma cell invasion and intravasation by secreting EGF and remodeling ECM architecture. Carcinoma cells also secrete CSF-1
to recruit macrophages to the site of intravasation. (b) Time-lapse images taken by intravital imaging of a GFP-labeled mammary tumor
showing a carcinoma cell on blood vessel wall as it extends an invadopodium-like protrusion into the blood space (arrowheads). Blood vessels
are seen as non-fluorescent regions. The dotted line indicates the cell outline.

tumor and the surrounding tissue. The presence of tumor-
associated macrophages in primary tumors has been
associated with increased metastasis [10]. Using a che-
motaxis-based in vivo invasion assay, it was revealed that a
paracrine loop between carcinoma cells and macrophages
facilitates invasion of carcinoma cells in the primary
tumor [11]. In the in vivo invasion assay, when micro-
needles filled with Matrigel containing EGF were
inserted into a mammary tumor, not only carcinoma cells
but also macrophages migrated into the needles. When
colony-stimulating factor 1 (CSF-1), a chemoattractant for
macrophages, was used instead of EGF in this assay, the
same cell types were collected again. Expression analysis
showed that macrophages express CSF-1 receptor and
secrete EGF, whereas carcinoma cells express EGF
receptor and secrete CSF-1. Thus, these two cell types
reciprocally induce each other to migrate [11]. This
paracrine loop was further confirmed by reconstitution
of invasion in vitro in a 3D culture system [12]. When
carcinoma cells were co-cultured with macrophages in 3D
collagen gels, invasion of both cell types was enhanced in
an EGF- and CSF-1-dependent manner. Intravital ima-
ging also demonstrates that carcinoma cells tend to intra-
vasate into the blood stream through sites on blood vessel
walls where tumor-associated macrophages form clusters
(J Wyckoff, unpublished). As macrophages are able to
degrade ECM through a specialized structure called
podosome, they may generate a local microenvironment
that is favorable for cancer cells to invade and intravasate
by modifying ECM structures (Figure 1a). Cleavage of

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ECM by matrix proteinases produces bioactive frag-
ments, including some chemoattractants for carcinoma
cells [13]. Therefore, macrophages could also contribute
to chemotaxis of carcinoma cells by releasing chemotactic
peptides through podosome-mediated ECM proteolysis.
Cell protrusions for cell migration in tumors:
lamellipodia and invadopodia/podosomes
The initial step in cell migration is the protrusion of the
cell membrane. This is driven by localized actin poly-
merization [14] and can occur in response to chemotactic
signals [15]. Carcinoma cells crawling on ECM fibers in
primary tumors extend pseudopods that attach to the
fibers at the migration front [7]. The pseudopods seem
to be functionally equivalent to lamellipodia (sheet-like
protrusions observed in cells migrating on 2D substrate in
vitro), although the shapes of pseudopods are more three
dimensional in vivo [9]. Leading protrusions attach to
collagen-containing fibers, a process that may involve the
dynamic adhesion structures called focal complexes. The
upregulation in invasive tumor cells of the expression of
adhesion molecules such as laminins and integrins [3,9]
is consistent with the importance of integrins in Rac1
stimulation, adhesion formation and cell migration in
invasive tumor cells [16].
The protrusion activity of invasive tumor cells is
enhanced by their upregulation of the genes responsible
for EGF-stimulated protrusions, namely the genes coding
for the cofilin, capping protein and Arp2/3 complex path-
ways [3,4]. The significance of this pattern of expression
in invasive tumor cells may be understood when one
considers that the cofilin pathway is directly involved
in directional sensing during chemotaxis of carcinoma
cells to EGF [17], and that cofilin is sufficient to set the
direction of cell movement [18]. Directional sensing of
EGF requires a burst of generation of free, actin filament
barbed ends resulting from cofilin severing that causes
localized actin polymerization [17]. If the free barbed end
formation is either inhibited or sustained, then directional
protrusion in response to EGF fails. The cofilin-depen-
dent actin polymerization has also been shown to act in
synergy with the Arp2/3 complex to generate protrusions
in response to EGF that are responsible for cell migration
[15,19].
To migrate through a physical barrier of dense ECM,
cancer cells need to extend protrusions with an ability to
remodel and degrade ECM. This type of protrusion is
particularly important for the invasion of cancer cells
through the basement membrane covering blood vessels.
Invasive cancer cells cultured on physiological substrates
form actin-rich membrane protrusions extended verti-
cally from the ventral cell membrane. These structures
have been termed invadopodia, because they have a
matrix degradation activity. Invadopodia are enriched
with actin regulatory proteins, adhesion molecules, sig-
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Cell migration in tumors Yamaguchi, Wyckoff and Condeelis 561
naling/adaptor proteins, membrane remodeling proteins
and matrix degrading proteases [20,21,22–26,27]
(Figure 2). Invadopodium formation has been observed
only in highly invasive cancer cells and is therefore
implicated in tumor cell metastasis. EGF has been shown
to stimulate invadopodium formation in carcinoma cells,
indicating that invadopodium formation is regulated by
chemotactic and invasive signals [27]. Podosomes are
dynamic actin-rich adhesion structures that have remark-
able similarity to invadopodia in molecular composition.
Podosomes are formed by monocyte-derived cells, such
as macrophages, as well as by some non-hematopoietic
cells and by transformed fibroblasts [28].
Key molecules for the formation of podosomes and inva-
dopodia are WASP (Wiskott-Aldrich Syndrome protein)
and N-WASP (neural WASP). WASP and N-WASP are
WASP family proteins that induce the rapid actin poly-
merization required for formation of cell protrusions
[29–31]. WASP has been shown to regulate podosome
formation in macrophages, dendritic cells and osteoclasts
[28,32]. N-WASP is a component of podosomes and
invadopodia in non-hematopoietic and cancer cells
[27,28,33–35]. Several upstream activators of N-WASP/
WASP, including Cdc42, Nck1 and WIP, and a down-
stream effector, the Arp2/3 complex, have been shown to
function in invadopodium/podosome formation [21,
27,28,33,36,37]. Thus, the WASP/N-WASP signaling
pathway is likely to have a role in ECM remodeling via
the formation of podosomes and invadopodia and, hence,
in tumor invasion and metastasis. Supporting this hypoth-
esis, our pilot experiments have shown that mammary
tumors of the rat derived from carcinoma cells expressing
dominant-negative N-WASP have a reduced ability to
intravasate and spontaneously metastasize (H Yamaguchi,
unpublished).
Although there are many similarities between invadopo-
dia and podosomes, their precise relationship has been
obscured by the fact that most podosome studies have
used cells on non-physiological surfaces such as glass,
whereas studies of invadopodia are classically carried out
on thick ECM. Given that this might lead to an artificial
distinction between the two structures, it has been pro-
posed that podosomes are precursor structures that
mature into more stable invadopodia under certain phy-
siological conditions [21,27]. This is supported by evi-
dence that podosomes show an ECM degradation activity
on physiological substrates [28,38–40]. Recent studies
using time-lapse microscopy revealed that podosomes are
dynamic structures with a life span of minutes, whereas
invadopodia have lifetimes that vary from minutes to
hours [27,41,42]. Interestingly, invadopodia with long
lifetimes are more stationary than short-lived invadopo-
dia, suggesting that stable functional invadopodia mature
from dynamic motile precursors that are conceivably
equivalent to podosomes. This maturation process
Current Opinion in Cell Biology 2005, 17:559–564
562 Cell–to–cell contact and ECM

Figure 2

Model of carcinoma cell migration on and through the extracellular matrix (ECM). (a) Highly motile carcinoma cells use dynamic adhesion
structures, focal complexes and podosome-type invadopodia precursors for migration on the ECM. In response to invasive signals, these
structures mature into stable invadopodia when cells migrate through rigid ECM. N-WASP nucleates actin filaments to initiate invadopodium/
podosome formation and also induce actin network formation synergistically with cofilin at the base to anchor and stabilize invadopodia.
(b) The molecular components of invadopodia.

appears to require integrin activation, concentration of
matrix proteinases, and stabilization via the formation of
actin network by the actin polymerization machinery.
FRET (fluorescence resonance energy transfer) analyses
with an N-WASP biosensor demonstrated that N-WASP
is transiently activated at the base of active invadopodia
[43]. Cofilin, a critical initiator of actin polymerization in
response to EGF, has been shown to determine the site of
actin polymerization and, in synergy with Arp2/3 com-
plex, to enhance dendritic nucleation [15]. Cofilin knock-
down results in the formation of less invasive invadopodia
with short lifetimes, indicating that cofilin is required for
maturation of invadopodia [27]. Therefore, N-WASP/
Arp2/3 complex and cofilin seem to cooperatively induce
actin polymerization at the base of invadopodia to anchor
and stabilize invadopodia (Figure 2).
Macrophage podosomes are formed at the leading lamel-
lipodia and are thought to function in adhesion site
formation, which is required for chemotaxis [28,42].
Interestingly, focal adhesions in smooth muscle cells
are remodeled into podosomes at the cell periphery in
response to phorbol ester, a potent tumor promoter [37].
Given that focal complexes/adhesions and podosomes
share major structural components, it is possible that
podosomes are converted from focal complexes/adhe-
sions upon cell migratory signals. This is consistent with
the fact that transformation of fibroblasts by oncogenic
Src or Ras disassembles focal adhesions and stress fibers
and induces the formation of podosomes, a process that is
associated with increased cell motility and invasion
[44,45]. Taken together, focal complexes mainly mature
into stable focal adhesions associated with stress fibers in
strongly adherent, slow-migratory cells, whereas in highly
motile and invasive cells these structures are converted to
dynamic podosomes/invadopodia precursors, and can
subsequently mature into functional invadopodia that
allow cells to invade and degrade ECM barriers
(Figure 2).
Conclusions
Mechanisms of cell migration in tumors have been
unveiled by the use of new technologies such as intravital
imaging and in vivo invasion assays. In vitro studies using
3D cell culture systems have revealed new aspects of
cancer cell migration and focused our attention on spe-
cialized protrusions involved in chemotaxis and ECM
invasion. Nevertheless, 2D cell culture still provides
important insights into the molecular basis of cell protru-
sions, chemotaxis and cell polarity. Therefore, the inte-
gration of in vivo, in vitro, 3D, and 2D observations will be
required to describe mechanisms of cancer cell migration
precisely. Integration of these approaches has already led
to a better understanding of the relationships between
and importance of podosomes and invadopodia. Future
advances using these combined approaches will hopefully

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lead to the development of a new generation of anti-
cancer drugs that target cell motility.
Acknowledgements
We apologize to those authors whose work we were unable to cite
because of space and date of publication limitations. We are grateful
to all laboratory members and collaborators for their support and helpful
discussions. We thank M Sidani for intravital imaging pictures. This work
was supported by grants from the NIH (GM38511 and CA100324).
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